Cornuside as a promising therapeutic agent for diabetic kidney disease: Targeting regulation of Ca2+ disorder-mediated renal tubular epithelial cells apoptosis

Renal tubular epithelial cells (RTECs) apoptosis is the key factor in the development of diabetic kidney disease (DKD). Endoplasmic reticulum stress (ERS) leading to mitochondrial Ca2+ overload is one of the causes of apoptosis in RTECs. Corni Fructus (CF) is an herbal medicine, developed and applied as a functional food, and it is commonly used to treat DKD. Cornuside (Cor) is one of the main chemical components in CF. This research seeks to investigate the function of Cor in DKD and delve into its possible mechanisms. Cor significantly improved renal function and ameliorated renal pathological changes of db/db mice. Bioinformatics analyses suggested that the modulation of endoplasmic reticulum-induced intrinsic apoptosis pathway was a primary mechanism by which Cor ameliorated DKD. TUNEL assays and flow cytometry assays indicated that Cor effectively inhibited RTECs apoptosis in db/db mice and AGE-induced HK-2 cells. Further experimental studies showed that Cor mitigated ERS by inhibiting the activation of PERK/ATF4/CHOP signal pathway and down-regulation of VDAC1 protein expression, thus alleviating mitochondrial Ca2+ overload. More importantly, Cor directly targeted NEDD4 to facilitate VDAC1 degradation. Notably, the silencing of NEDD4 nearly abolished Cor's inhibitory effects on mitochondrial Ca2+ overload and apoptosis. In conclusion, Cor modulated Ca2+ homeostasis by alleviating ERS and targeting NEDD4, thus mitigating apoptosis of RTECs in DKD. These findings indicate that Cor has the potential for the treatment and drug development of DKD.